We report here the antibacterial activity of the new penem antibiotic Men 10700 against a total of 740 gram-positive and gram-negative clinical isolates, in comparison to imipenem, meropenem, cefotaxime, ceftriaxone, ciprofloxacin and gentamicin. Men 10700 has shown a wide spectrum of antibacterial activity, with a potent activity both against gram-positive species (with the exception of methicillin-resistant Staphylococcus aureus and Staphylococcus epidermidis) as indicated by minimal inhibitory concentration (MIC(90)) values < or =0.5 mg/l, and gram-negative species, with MIC(90) values generally < or =2 mg/l. Men 10700 was the most potent antibiotic against methicillin-susceptible S. aureus and S. epidermidis, while the overall spectrum of activity resembled that of imipenem; meropenem was more active against most gram-negative species. In comparison with third-generation cephalosporins, Men 10700 demonstrated superior activity against methicillin-susceptible S. aureus and S. epidermidis and some gram-negative species such as Morganella morganii, Serratia spp. and Enterobacter cloacae; moreover, in contrast to third-generation cephalosporins, Men 10700 showed moderate activity against Enterococcus spp. The activity of Men 10700 against penicillin-resistant Streptococcus pneumoniae (10 strains) and some gram-negative strains selected for their resistance to cefotaxime (20 strains) was particularly interesting.

Anti-Bacterial Agents↗

PubMedDate not supplied

In vitro comparative dynamics of modified-release clarithromycin and of azithromycin.

Antibacterial kinetics of modified-release clarithromycin (CLA) and azithromycin (AZI) against respiratory tract pathogens were compared in relation to their pharmacokinetic profile. The study was carried out in three strains of Streptococcus pneumoniae, group A beta-hemolytic Streptococcus pyogenes, Moraxella catarrhalis and Haemophilus influenzae, respectively, exposed to concentration gradients of CLA and AZI simulating human serum pharmacokinetics after administration of 500 mg p.o. in a single dose. Bactericidal kinetics were assessed by counting the number of survivors before each change in concentration over a period of 36 h. The minimal inhibitory concentrations (MICs) of CLA and AZI were evaluated at time 0 and after 36 h of exposure to antibiotics in the surviving organisms. The results showed that CLA and AZI, in the experimental conditions adopted, had different antibacterial kinetics. Moreover, the addition of the 14-OH metabolite of CLA at the same concentrations reached in human serum exerted a bactericidal effect against two strains of H. influenzae resistant to CLA and AZI. An increase in MICs was observed against S. pyogenes and H. influenzae, with higher values for AZI.

Anti-Bacterial Agents↗

PubMedDate not supplied

Melatonin involvement in immunity and cancer.

The most studied endocrine product of the pineal gland, melatonin, has been reported to be involved in the feedback between neuroendocrine and immune functions and to exert oncostatic action, at least in certain experimental conditions. Melatonin seems to be an integral part of the immune system, by exerting direct and/or indirect stimulatory effects on both cellular and humoral immunity. Likewise, an antitumor activity of melatonin has been shown in several experimental models in vivo and in vitro. The means by which melatonin exerts its effects on immunity and neoplastic growth have not been elucidated. The different putative mechanisms of action of melatonin investigated so far are here briefly discussed.

Adjuvants, Immunologic↗

PubMedDate not supplied

Methods for the evaluation of drug action at the human melatonin receptor subtypes.

NIH3T3 fibroblast cells transfected with the full-length coding regions of the mt1 and MT2 human melatonin receptors stably expressed the receptor, coupled to a pertussis-toxin-sensitive G protein and exhibiting high affinity for melatonin. Both mt1 and MT2 melatonin receptors mediated the incorporation of [35S]GTPgammaS into isolated membranes via receptor-catalyzed exchange of [35S]GTPgammaS for GDP. The relative intrinsic activity and potency of the compounds were subsequently studied by using [35S]GTPgammaS incorporation. The order of potency was equal to the order of apparent affinity. Melatonin and full agonists increased [35S]GTPgammaS binding. Luzindole did not increase basal [35S]GTPgammaS binding but competitively inhibited melatonin-stimulated [35S]GTPgammaS binding, thus exhibiting antagonist action. Two other mt1 antagonists, 4P-PDOT and N-[(2-phenyl-1H-indol-3-yl)ethyl]cyclobutanecarboxamide, behaved as partial agonists at the MT2 subtype, with relative intrinsic activities of 0.37 and 0.39, respectively. For the first time, these findings show important differences in analogue intrinsic activity between the human mt1 and MT2 melatonin receptor subtypes.

3T3 Cells↗

PubMedDate not supplied

Melatonin influences human balance.

In order to evaluate a possible correlation between melatonin, the cerebellum and, consequently, human balance, a double-blind pilot study was performed in 5 subjects with random administration of different doses of melatonin. Before and 1 h after a single administration, a complete otoneurological examination was performed. This first pilot study revealed that melatonin had effects on human equilibrium although these effects were not dosage related and were different in individual subjects. On the basis of these results, a second study was performed. Fourteen healthy volunteers were investigated before and 1 h after administration of a single dose of 10 mg melatonin. The otoneurological examination was restricted to the evaluation of: horizontal saccades, horizontal sinusoidal smooth pursuit, eyes open, eyes closed and head retroflexed static posturography. All subjects showed a decrease in posturographic performances, especially in the simplest test (eyes open) and half of them (6 out of 13) showed also impairment of eye movements. These results confirm the role of melatonin in the control of sensorimotor performances, and the cerebellar receptors might be correlated with the control of human balance.

Adult↗

PubMedDate not supplied

A new model examining intracellular and extracellular activity of amoxicillin, azithromycin, and clarithromycin in infected cells.

An in vitro infection model was created using a suspension of macrophages, polymorphonuclear leukocytes, lymphocytes, fibroblasts, and human serum to which pathogen and antibiotic were added. Separate intracellular and extracellular antibiotic concentrations and activity against Staphylococcus aureus and Legionella pneumophila were assessed for three antimicrobial agents: amoxicillin, azithromycin and clarithromycin. Amoxicillin was found almost exclusively in extracellular fluid, where it was active; intracellularly, it was ineffective. Azithromycin, in contrast, was primarily concentrated and active intracellularly, with little activity in extracellular fluid. Clarithromycin was present in both compartments and possessed significant activity both intracellularly and extracellularly.

Amoxicillin↗

PubMedDate not supplied

Effect of antibiotics on Bordetella pertussis adhering activity: hypothesis regarding mechanism of action.

Microbial adherence to epithelial cell surfaces has been implicated as the first step in the initiation of several infectious diseases. The ability of antibiotics to affect the properties of bacterial adherence to cell surfaces may be a criterion in selecting antibiotics for therapy. This study was performed in order to investigate the activity of amoxicillin, chloramphenicol, and clarithromycin in modifying the adhering activity of Bordetella pertussis to human epithelial cells. The actions of antibiotics, alone or combined with aprotinin, were compared with that of trypsin, aprotinin and trypsin+aprotinin, to investigate the chemical nature of the ligand where antibiotics could act. The adhering activity was evaluated on human epithelial cells, collected from the oral mucosa, challenged with B. pertussis A2963 previously incubated in the presence of the tested substances for 1 h at 37 degrees C in a shaker incubator. After staining, the percentage of mucosal cells with more than 50 adhering bacteria was evaluated. Under the described experimental conditions, trypsin significantly reduced the adherence of B. pertussis. Aprotinin had no effect but was able to counteract the inhibitory action of trypsin. Both clarithromycin and chloramphenicol markedly reduced adhering activity and their actions were not counteracted by aprotinin. Amoxicillin was without effect. It was hypothesized that chloramphenicol and clarithromycin, exerting their antimicrobial action by inhibiting bacterial protein synthesis, affected bacterial adhesion through an unknown mechanism without proteolytic effect.

Amoxicillin↗

PubMedDate not supplied

Concentrations of ceftibuten in bronchial secretions.

Ceftibuten is a broad-spectrum oral cephalosporin exhibiting antimicrobial activity against a wide range of gram-negative and some gram-positive pathogens. Pharmacokinetic studies have shown that the molecule has an oral bioavailability higher than 90% of the administered dose (reaching peak serum concentrations of 5-19 mg/l after a single dose of 200 and 400 mg). Moreover, ceftibuten has been shown to be useful in the treatment of acute lower respiratory tract infections. This study was performed to determine the distribution of ceftibuten in bronchial secretions from patients affected by the exacerbation of chronic bronchitis. Patients were treated with a single 400-mg oral dose of ceftibuten. Blood and bronchial-secretion samples were obtained just before, and at 0.5, 1, 2, 4, 8, 12, 16 and 24 h after dosing. Cells were separated from bronchial secretions by centrifugation. Ceftibuten in duplicate samples of both serum and bronchial secretion was quantified by HPLC. Ceftibuten reached peak levels 2 and 4 h after oral administration in serum and in bronchial secretions, respectively (18.12 +/- 2.13 and 9.19 +/- 3.1 mg/l, respectively). Falling curves after the peaks showed a monoexponential decay. The absorption was very rapid both in serum and bronchial secretions, but elimination was slower in bronchial secretions than in serum.

Administration, Oral↗

PubMedDate not supplied

Bactericidal kinetics of an in vitro infection model of once-daily ceftriaxone plus amikacin against gram-positive and gram-negative bacteria.

The in vitro efficacy of ceftriaxone plus amikacin combination against gram-positive and gram-negative bacteria, clinically isolated from patients affected by pneumonia in intensive care units, was compared to that of the 2 drugs used alone. The study was performed using a dynamic model in which the human kinetics of the drugs after intramuscular administration was simulated. The antibacterial activity was tested by determining the bacterial cell count (CFU/ml). Killing curves came out from plotting the log CFU/ml versus time. In the same way, ceftriaxone and amikacin concentrations were assayed by HPLC and fluorescence polarization immunoassay, respectively. The results show that ceftriaxone plus amikacin combination exert a high killing activity against all tested strains. The two antibiotics alone initially have a good killing activity but this is followed by bacterial regrowth for all tested isolates. This data supports the results of several clinical studies which have shown a good therapeutic efficacy of ceftriaxone plus amikacin combination in the treatment of severe infections caused by organisms intermediately sensitive to these drugs.

Amikacin↗

PubMedDate not supplied

Comparison of miocamycin versus amoxycillin in lower respiratory tract infections in children. Clinical response and effect on natural killer activity.

The clinical efficacies of 50 mg/kg.day miocamycin and 60 mg/kg.day amoxycillin were studied in 23 patients aged 3-11.5 years with presumed bacterial infection of the lower respiratory tract (bronchopneumonia and acute bronchitis). During the therapy, which continued for 10 days, non-specific immune function, represented by natural killer cell activity, was monitored by measurement of the rate of lysis induced on target K-562 51Cr-labelled tumour cells. The results confirmed the therapeutical efficacy of miocamycin and amoxycillin in the oral therapy of bronchopneumonia and acute bronchitis in paediatric patients. The natural killer cell activity of patients treated with miocamycin was increased on days 7 and 10 of therapy compared with baseline. This finding did not occur in patients treated with amoxycillin.

Acute Disease↗

PubMedDate not supplied

Clinical efficacy and tolerance of two new macrolides, clarithromycin and josamycin, in the treatment of patients with acute exacerbations of chronic bronchitis.

The efficacy and safety of oral 500 mg clarithromycin given twice daily and 500 mg josamycin given three times daily were compared for up to 14 days in the treatment of 103 out-patients with acute exacerbations of chronic bronchitis in an open, randomized study. The predominant pathogens isolated were Streptococcus pneumoniae, Haemophilus influenzae and Staphylococcus aureus. Clinical cures were experienced by 85% of the clarithromycin-treated patients, with an additional 10% showing improvement. In josamycin-treated patients, 76% of the patients experienced clinical cures and an additional 19% showed improvement. Eradication of the causative pathogen occurred in approximately 95% of the patients in both treatment groups. Adverse events, which all involved the gastro-intestinal tract and were mild, transient and probably related to therapy, were experienced by 5.8% and 7.8%, respectively, of the clarithromycin- and josamycin-treated patients. It is concluded that clarithromycin given twice daily is as effective as josamycin given three times daily.

Adolescent↗